Xanthine Oxidase Inhibition Attenuates Endothelial Dysfunction Caused by Chronic Intermittent Hypoxia in Rats

Background: Xanthine oxidase is a major source of superoxide in the vascular endothelium. Previous work in humans demonstrated improved conduit artery function following xanthine oxidase inhibition in patients with obstructive sleep apnea. Objectives: To determine whether impairments in endothelium-dependent vasodilation produced by exposure to chronic intermittent hypoxia are prevented by in vivo treatment with allopurinol, a xanthine oxidase inhibitor. Methods: Sprague-Dawley rats received allopurinol (65 mg/kg/day) or vehicle via oral gavage. Half of each group was exposed to intermittent hypoxia (FIO(2) = 0.10 for 1 min, 15x/h, 12 h/day) and the other half to normoxia. After 14 days, gracilis arteries were isolated, cannulated with micro-pipettes, and perfused and superfused with physiological salt solution. Diameters were measured before and after exposure to acetylcholine (10(-6) M) and nitroprusside (10(-4) M). Results: In vehicle-treated rats, intermittent hypoxia impaired acetylcholine-induced vasodilation compared to normoxia (+4 +/- 4 vs. +21 +/- 6 mu m, p = 0.01). Allopurinol attenuated this impairment (+26 +/- 6 vs. +34 +/- 9 mu m for intermittent hypoxia and normoxia groups treated with allopurinol, p = 0.55). In contrast, nitroprusside-induced vasodilation was similar in all rats (p = 0.43). Neither allopurinol nor intermittent hypoxia affected vessel morphometry or systemic markers of oxidative stress. Urinary uric acid concentrations were reduced in allopurinol- versus vehicle-treated rats (p = 0.02). Conclusions: These data confirm previous findings that exposure to intermittent hypoxia impairs endothelium-dependent vasodilation in skeletal muscle resistance arteries and extend them by demonstrating that this impairment can be prevented with allopurinol. Thus, xanthine oxidase appears to play a key role in mediating intermittent hypoxia-induced vascular dysfunction. Copyright (C) 2011 S. Karger AG, Basel